Is CHRND p.Ser166Phe (c.497C>T) pathogenic?

CHRND p.Ser166Phe (c.497C>T) is classified Uncertain significance in CHRND (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-07-30). AlphaMissense: likely pathogenic (0.8235); Rare (popmax 0.113%, sas); Associated with lethal multiple pterygium syndrome.

What condition is associated with CHRND p.Ser166Phe (c.497C>T)?

CHRND p.Ser166Phe (c.497C>T) is associated with lethal multiple pterygium syndrome, congenital myasthenic syndrome 3A (ClinVar).

How common is CHRND p.Ser166Phe (c.497C>T) in the general population?

CHRND p.Ser166Phe (c.497C>T) is rare (popmax 0.113%, sas) (gnomAD).

What do computational predictors say about CHRND p.Ser166Phe (c.497C>T)?

AlphaMissense predicts likely pathogenic (score 0.8235) — an in-silico prediction, not a clinical call.

CHRND p.Ser166Phe

c.497C>T · rs528286132 · VCV290021

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8235 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.113%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lethal multiple pterygium syndrome

Computational evidence

Protein change
AlphaMissense	0.8235	likely pathogenic
REVEL	0.693	pathogenic-leaning
SaProt	LLR -11.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 9,093 bp · p 0.12 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.113% South Asian · 103/91,080 alleles

Filtering AF 0.0953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0888%

Overall 0.00694% 112/1,614,030 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.113%	884
Remaining individualsnot grpmax-eligible	0.0144%	6,946

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CHRND
Protein: p.Ser166Phe
Coding: c.497C>T
MANE Select: NM_000751
dbSNP: rs528286132
Type: single nucleotide variant
Location: chr2:232528644 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 25 PDB
Residue 166: a β-strand

Full CHRND gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lethal multiple pterygium syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 3A

Similar variants

CHRND c.1252+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHRND c.821-2A>C Pathogenic/Likely pathogenic ★★ same condition
CHRND c.933-2A>G Likely pathogenic ★★ same condition
CHRND p.Arg336Gln Likely pathogenic ★★ same condition
CHRND p.Arg43Trp Pathogenic/Likely pathogenic ★★ same condition
CHRND p.Cys257Arg Pathogenic/Likely pathogenic ★★ same condition
CHRND p.Trp78Ter Pathogenic ★★ same condition
CHRND p.Trp83Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/chrnd-p-ser166phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown